Patent GB-809494-A (GB)
Title: Androstene derivatives
IPC: C12P33/00
Filed: 1957-05-30
Abstract: The invention comprises 1a -hydroxy androstene derivatives of the formula <FORM:0809494/IV (b)/1> wherein the carbon in the 5-position is attached by a double bond to either the carbon in the 4-position or to the carbon in the 6-position, X is a carbonyl, hydroxymethylene or esterified hydroxymethylene group, Y is an hydroxy or esterified hydroxy group, and Z is a carbonyl, hydroxymethylene, esterified hydroxymethylene or =C(OH) (lower alkyl) group, the alkyl group containing at most eight carbon atoms.  The hydroxyl groups may be esterified with alkanoic acids, e.g. formic, acetic, propionic, butyric, valeric, hexanoic, heptanoic and octanoic acids, their branched-chain isomers and cyclic analogues, or with alkane sulphonic acids, e.g. methane, ethane and propane sulphonic acids, forming mono-, di-, tri-esters including mixed esters.  The 1a -hydroxy steroids are prepared from the corresponding 1-unsubstituted steroids or their D 1-analogues by subjecting them to the action of enzymes of Penicillium sp. ATCC 12,556 cultivated aerobically.  The steroid may be added to a culture medium of the organism or treated with the separated oxygenating enzymes according to known procedures. Subsequent transformations may then be carried out, e.g. reduction of a 17-keto group with an alkali metal hydride, or reaction with an organometallic reagent to yield a 17a -alkyl-17b -ol compound, selective or complete esterification of the hydroxyl groups present, conversion to the 1b -hydroxy isomers by oxidation and then reduction of the resulting 1-oxo compound, or oxidation (Oppenauer) to a D 1,6-3-keto steroid, or direct conversion to estrone by pyrolysis.  In examples: (1) D 6-androstene-3,17-dione in ethanol is added to a medium containing aerobically cultivated Penicillium ATCC 12,556 and after 40 hours the mixture is extracted with methylene chloride and chromatographed on silica, whereupon elution with ethyl acetate-benzene gives 2b -hydroxy - D 6 - androstene - 3,17 - dione and then 1a  - hydroxy - D 6 - androstene - 3,17 - dione, which is converted (2) to the acetate and (3) to the butyrate; (4) 1,4-androstadiene-3,17-dione treated as in (1) yields 1a -hydroxy-4-androstene-3,17-dione; whilst (5) dehydroisoandrosterone gives mainly 1a ,3b -dihydroxy-5-androsten-17-one, which (6) to (9), is converted into its 3-monoacetate, 1,3-diacetate, 1,3-dimesylate, 1,3-di-ethanesulphonate and 1-mesylate-3-acetate; (10) reduction of 1a ,3b -dihydroxy-5-androsten-17-one with LiAlH4 gives 5-androstene-1a ,3b ,17b -triol and subsequently (11), its triacetate and tripropionate; (12) and (13), 1a ,3b -dihydroxy-5-androsten-17-one is treated with methyl or ethyl magnesium bromide yielding the corresponding 17-methyl or 17-ethyl-5-androstene - 1a ,3b ,17b  - triol; (14) oxidation of 1a  - hydroxy - 3b  - acetoxy - 5 - androsten - 17 - one with CrO3-pyridine, and LiAlH4 reduction of the resulting 3b -acetoxy-5-androstene-1,17-dione gives 5-androstene - 1b ,3b ,17b  - triol, which (15) is acetylated to the triacetate; (16) 1a ,3b  - dihydroxy - 5 - androsten - 17 - one after protection of the keto group and selective acetylation of the 3-hydroxyl similarly yields 1b ,3b  - dihydroxy - 5 - androsten - 17 - one and its 1-monoacetate and 1,3-diacetate.